The American Journal of Surgery (2008) 196, 562565

The American Society of Breast Surgeons

Sentinel lymph node biopsy in patients with

multicentric/multifocal breast cancer: low false-negative
rate and lack of axillary recurrence
Dana M. Holwitt, M.D.a, William E. Gillanders, M.D.a, Rebecca L. Aft, M.D., Ph.D.a,b,
Timothy J. Eberlein, M.D.a, Julie A. Margenthaler, M.D.a,*
a

Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA; bDepartment of Surgery, John
Cochran Veterans Hospital, St. Louis, MO, USA
KEYWORDS:
Breast Cancer;
Multicentric;
Multifocal;
Sentinel lymph node
biopsy

Abstract
BACKGROUND: Accuracy of sentinel lymph node biopsy (SLNB) and rate of axillary recurrence in
multicentric/multifocal (MC/MF) breast cancer are reported.
METHODS: From 1999 to 2006, 93 patients with MC/MF breast cancer underwent SLNB; 41
underwent axillary lymph node dissection regardless of SLN pathology (group 1), and 52 underwent
axillary lymph node dissection only if an SLN was positive (group 2). Patient demographics, SLN
techniques, and pathology were recorded.
RESULTS: There were no differences between the 2 groups with respect to patient age; tumor size,
grade, stage, and histology; or method of SLN detection. The incidence of axillary metastasis was
greater in group 1 patients (68%) compared with group 2 patients (12%) (P .01). In group 1, the
sensitivity and specificity of SLNB were 93% and 100%, respectively, with a false-negative rate of 7%.
None of the 52 patients in group 2 experienced axillary recurrence (median follow-up 4.8 years).
CONCLUSIONS: The accuracy of SLNB in MC/MF breast cancer is comparable with that observed
in unifocal breast cancer. Despite a lower rate of SLN positivity in patients undergoing SLNB only,
axillary recurrence was not observed.
2008 Elsevier Inc. All rights reserved.

Sentinel lymph node biopsy (SLNB) has emerged as the

standard method of axillary staging in breast cancer patients
with clinically negative axillas.13 The goal of SLNB is to
minimize morbidity while maintaining high sensitivity and
a low false-negative rate, such that axillary staging is similar
to the standard provided by axillary lymph node dissection
(ALND) pathology. Absolute and relative contraindications
for the use of SLNB have been proposed, including previous
mastectomy, previous axillary surgery or previous SLNB,
* Corresponding author. Tel.: 1-314-747-9724; fax: 1-314-4545509.
E-mail address: margenthalerj@wudosis.wustl.edu
Manuscript received April 10, 2008; revised manuscript June 4, 2008

0002-9610/$ - see front matter 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjsurg.2008.06.009

palpable lymphadenopathy, previous excisional breast biopsy, T3 and T4 tumors, male breast cancer, neoadjuvant
chemotherapy, and multicentric/multifocal (MC/MF) breast
cancers.19 However, as surgeon experience with SLNB has
progressed, the previously described contraindications for
SLNB have been challenged.
MC breast cancer is defined as 2 tumors arising in
different quadrants of the breast, whereas MF breast cancer
is used to describe 2 foci of invasive breast cancer within
the same quadrant.4 The diagnosis of MC/MF breast cancer
has been a relative contraindication to SLNB secondary to
concerns that there may be multiple dominant lymphatics
draining from each individual tumor to the axilla.9 The
lymphatics may drain to a different SLN for each tumor

D.M. Holwitt et al.

Sentinel node biopsy in multicentric/multifocal breast cancer

present such that SLN mapping may only identify the drainage of 1 tumor and miss the SLN associated with the other
tumors present.39 However, this is inconsistent with reports
that a single, retroareolar injection of tracer and/or blue dye
is comparable with a peritumoral injection in reliably identifying the SLN for patients with unifocal breast cancer.4 10
An additional concern regarding the use of SLNB for patients with MC/MF invasive breast cancer is that the identification of all involved SLN(s) may be less likely, leading
to higher axillary recurrence rates. The aim of the current
study was to examine the accuracy of SLNB in MC/MF
breast cancer and the rate of axillary recurrence.

Patients and Methods

Institutional Review Board approval was obtained before
the commencement of this retrospective study. Written informed consent of patients was not required. The prospectively maintained surgical database at Washington University/Barnes Jewish Hospital was queried from January 1,
1999, to December 31, 2006, to identify all patients with a
diagnosis of biopsy-proven MC/MF invasive breast cancer
who underwent SLNB with or without concurrent ALND
(n 93). Patients who underwent ALND without SLNB
were excluded from the analysis (n 17). All patients
required mastectomy for local control. For statistical comparisons, patients were divided into 2 groups: (1) patients
who underwent completion ALND regardless of SLN pathology (n 41); and (2) patients who underwent ALND
only for a positive SLNB (n 52).
All SLNB procedures were performed with the patient
under general anesthesia. Standard SLNB techniques using
radiocolloid and/or blue dye injection were used for all patients. 99mTechnetium radiocolloid was injected peritumorally
in all patients by the nuclear medicine department at least 2
hours before the planned SLNB procedure. Five milliliters of
blue dye was injected either peritumorally or subareolar by the
operating surgeon 5 minutes before the planned SLNB procedure. All SLN(s) were identified with the gamma probe and/or
by identifying the blue-stained lymphatic.
Pathologic analysis of SLN(s) included staining with
hematoxylin and eosin and immunohistochemistry using a
monoclonal cytokeratin antibody mix. Analysis of nonSLN(s) removed during ALND included staining of bivalved lymph node sections only with hematoxylin and
eosin staining. Patient demographics, method of SLN localization, injection site, and final lymph node pathology were
recorded. Axillary recurrence was used as a surrogate for
the true status of the axilla for group 2 patients. All data
were transferred to a single spreadsheet (Excel; Microsoft,
Redmond, Washington). Statistical calculations were performed using software (StatView; Abacus Concepts, Berkeley, California). For all analyses, results were considered
statistically significant at P .05.

563

Results
Ninety-three patients were identified with clinically
node-negative MC/MF invasive breast cancer during the
study period. Of the 93 patients, 41 underwent ALND
regardless of SLN pathology (group 1), and 52 underwent
ALND only if the SLN was positive on final pathology
(group 2). From the retrospective review, this difference in
approach appeared to be attributed to surgeon discretion;
there were no identifiable clinical factors accounting for this
finding. A comparison of the demographic and histopathologic characteristics of the 2 groups is listed in Table 1.
There were no differences between the 2 groups with respect to patient age, tumor size, tumor grade, stage, and
histology; estrogen-receptor status, progesterone-receptor
status, or Her-2-neu status (P .05 for all). Method of SLN
detection (70% blue dye only, 3% radiocolloid only, and
27% blue dye plus radiocolloid) and site of injection of blue
dye (71% peritumoral and 29% retroareolar) and radiocolloid (100% peritumoral) was also similar between the 2
groups. Lymphovascular invasion was present in 35.7% of
patients in group 2 compared with only 19.6% of patients in
group 1, but this difference was not statistically significant.
The rate of postmastectomy radiation was high for both
groups (58.8% in group 1 and 71.1% in group 2) and was
not significantly different. We were unable to determine
retrospectively which patients underwent axillary field radiation as part of their postmastectomy radiation treatment.
There were no statistically significant differences in the
rates of systemic chemotherapy and/or endocrine therapy
use between the 2 groups.
The incidence of axillary metastasis was greater in those
patients who underwent planned ALND regardless of the SLN
results (group 1: 28 of 41 [68%]) compared with those who
underwent ALND only if the SLN was positive (group 2: 6 of
52 [12%]) (P .01). Of the 93 patients, 14 (15%) underwent
neoadjuvant therapy (group 1: 5 of 41 [12%] and group 2: 9 of
52 [17%]). Of the 14 patients who underwent neoadjuvant
therapy, 12 underwent axillary staging before neoadjuvant
therapy initiation (5 patients in group 1 and 7 patients in group
2). The 2 patients who did not undergo pretherapy axillary
staging were also in group 2 and were enrolled in neoadjuvant
endocrine therapy trials; 1 had a positive SLN after therapy,
and 1 had a negative SLN after therapy.
For patients in group 1, the sensitivity and specificity of
SLNB were 93% and 100%, respectively, with a falsenegative rate of 7%. The SLN was the only metastatic node
in 43% of group 1 patients. Six of the 52 patients in group
2 had a positive SLN and underwent completion ALND;
none of the patients within this group experienced axillary
recurrence at follow-up (median 4.8 years).

Comments
SLNB has been validated in unicentric, clinically nodenegative breast cancer and has become the standard of care

564

The American Journal of Surgery, Vol 196, No 4, October 2008

Table 1 Patient and tumor characteristics in 93

multicentric/multifocal invasive breast cancer patients
undergoing sentinel lymph node biopsy

Variable
Mean age (y)
Tumor size
T1
T2
T3
T4
Stage
I
II
III
IV
Tumor grade
I
II
III
Histology
IDC
ILC
Mixed
LVI
ER status
Positive
Negative
Unknown
PR status
Positive
Negative
Unknown
Her-2-neu status
Amplified
Nonamplified
Unknown
Method of SLN injection
Blue dye
Radiocolloid
Both
Site of injection
Blue dye
Retroareolar
Peritumoral
Radiocolloid
Peritumoral
XRT
Systemic chemotherapy
Yes
No
Endocrine therapy
Yes
No
Axillary metastasis

ALND only for

Planned
ALND (%) positive SLN (%)
n 52
P
n 41
54

59

NS
NS

28
9
2
2

(68)
(22)
(5)
(5)

43
8
0
1

(83)
(15)
(0)
(2)

11
21
9
0

(27)
(51)
(22)
(0)

36
14
2
0

(69)
(27)
(4)
(0)

NS

NS
3 (7)
17 (42)
21 (51)

11 (21)
31 (60)
10 (19)

33
4
4
10

40
8
4
15

NS
(80)
(10)
(10)
(20)

(77)
(15)
(8)
(36)

34 (83)
6 (15)
1 (2)

38 (73)
13 (25)
1 (2)

27 (66)
12 (29)
2 (5)

30 (58)
20 (38)
2 (4)

8 (19)
31 (74)
3 (7)

9 (17)
38 (73)
5 (10)

27 (66)
2 (4)
12 (30)

37 (71)
1 (2)
14 (27)

NS
NS

NS

NS

NS

NS
8 (16)
42 (84)

17 (33)
34 (67)

14 (100) 15 (100)
30 (58.8) 27 (71.1)
31 (76)
10 (24)

42 (81)
10 (19)

27 (66)
14 (34)
28 (61)

31 (59)
21 (41)
6 (12)

NS
NS
NS
.01

ER estrogen receptor; IDC invasive ductal cancer; ILC

invasive lobular cancer; LVI lymphovascular invasion; PR progesterone receptor; XRT radiation therapy.

for axillary staging in this patient population.13 The National Adjuvant Breast and Bowel Project (NSABP) B-32
trial was designed to demonstrate whether SLNB could

achieve the same diagnostic accuracy as the gold standard,

ALND, while significantly decreasing morbidity.11 In 5,600
patients enrolled in the NSABP B-32 trial, the SLN was identified successfully in 97.2% of patients, with overall accuracy
of 97.1% and a false-negative rate of 9.8%.11
Patients with MC/MF invasive breast cancers have
traditionally been considered to be poor candidates for
accurate axillary staging using SLNB. The main concern
regards the possibility of multiple dominant lymphatics
draining to 1 SLN, which may lead to a high falsenegative rate. Therefore, surgical therapy for patients
with MC/MF invasive breast cancer has traditionally included a modified radical mastectomy. Despite these concerns, several studies have demonstrated the validity of
SLNB in patients with MC/MF breast cancers.4 9 Concerns of disparate lymphatic drainage from MC/MF
breast cancers have been challenged by reports that the
breast drains to common SLN(s) through a small number
of common lymphatic channels regardless of the location
of the primary tumor.10 Furthermore, there appears to be
little effect of mapping-agent injection site on SLN identification rate, and studies have failed to show that any
one site of injection is superior to another.4 10 Our data
are consistent with these findings, where the overall SLN
identification rate was 100%, despite widely varying
methods of SLN mapping (blue dye plus/minus radiocolloid, retroareolar vs peritumoral injection).
Previous reports support the use of SLNB in patients
with MC/MF invasive breast cancers.4 9 Tousimis et al4
reported their experience in 70 patients with MC/MF
invasive breast cancer and clinically negative axillas who
required total mastectomy for local control. All 70 patients underwent SLNB followed by planned ALND regardless of SLN pathology, and the overall accuracy of
SLNB was 96%, with 93% sensitivity and a false-negative rate of 8%. Similarly, Kumar et al5 retrospectively
analyzed data from 48 patients with MF/MC breast cancer undergoing SLNB followed by ALND; they were able
to identify the SLN in 93.5% of patients, with 100%
sensitivity and a false-negative rate of 6%. In the current
study, patients who underwent planned ALND despite
SLN pathology (group 1) underwent successful SLNB
with 93% sensitivity and a 7% false-negative rate, which
is comparable with that observed in unicentric cancers.11
In our study, we observed that patients who underwent
a planned ALND after SLNB (group 1) had a significantly higher rate of node-positive disease than patients
who only underwent ALND if the SLNB was positive
(group 2). The reasons for this finding are unclear. It is
possible that the group 1 patients were selected to undergo planned ALND because of some clinical factor
predisposing to increased risk for lymph node metastasis,
although the 2 patient groups did not differ significantly
with regard to patient and tumor characteristics. An alternative explanation is that the false-negative rate of
SLNB in the group 2 patients is higher than that demon-

D.M. Holwitt et al.

Sentinel node biopsy in multicentric/multifocal breast cancer

strated in the group 1 patients, and we are simply unable

to identify this rate because the group 2 patients did not
routinely have ALND performed after SLNB. Although
we cannot measure this directly, using clinical axillary
recurrence as a surrogate marker for residual axillary
disease, there were no axillary recurrences in the 52
patients in group 2 during the follow-up period. Further,
axillary recurrence was not observed despite a relatively
high rate of lymphovascular invasion in group 2 patients
(35.7%). The impact of neoadjuvant therapy also did not
appear to significantly alter this rate of node positivity.
Axillary radiation and systemic therapies could in part
account for this lack of local recurrence, but there was no
difference in the use of postmastectomy radiation therapy
or systemic treatment modalities between the 2 groups.
Our findings are consistent with studies of SLNB in
unifocal breast cancer where the axillary recurrence rate
is low. It is unclear whether this is due to the accuracy of
the technique or the effectiveness of adjuvant therapies
and will only be answered by the results of randomized
clinical trials.
Despite these limitations, the current study demonstrates that SLNB in MC/MF clinically node-negative
breast cancer is feasible, with high sensitivity and specificity and low false-negative rates, similar to those observed in unicentric breast cancers. Further, the SLN
identification rate is independent of the site of mappingagent injection. No axillary recurrences were observed in
our patient population. Our data support the routine use
of SLNB for axillary staging in patients with clinically
node-negative MC/MF invasive breast cancer.

565

References
1. Krag D, Weaver D, Ashikaga T, et al. The sentinel node in breast
cancer: a multicenter validation study. N Engl J Med 1998;339:941 6.
2. Veronesi U, Paganelli G, Viale G, et al. Sentinel lymph node biopsy
and axillary dissection in breast cancer: results in a large series. J Natl
Cancer Inst 1999;91:368 73.
3. McMasters KM, Tuttle TM, Carlson DJ, et al. Sentinel lymph node
biopsy for breast cancer: a suitable alternative to routine axillary
dissection in multi-institutional practice when optimal technique is
used. J Clin Oncol 2000;18:2560 6.
4. Tousimis M, Van Zee K, Fey J, et al. The accuracy of sentinel lymph
node biopsy in multicentric and multifocal breast cancers. J Am Coll
Surg 2003;197:529 35.
5. Kumar R, Jana S, Heiba S, et al. Retrospective analysis of sentinel
node localization in multifocal, multicentric palpable or nonpalpable
breast cancer. J Nucl Med 2003;44:710.
6. Vlastos G, Rubio IT, Mirza NQ, et al. Impact of multicentricity on
clinical outcome in patients with T1-2, N0-1, M0 breast cancer. Ann
Surg Oncol 2000;7:5817.
7. Knauer M, Konstantiniuk P, Haid A, et al. Multicentric breast cancer:
a new indication for sentinel node biopsya multi-institutional validation study. J Clin Oncol 2006;24:3374 80.
8. Gentilini O, Trifiro G, Soteldo J, et al. Sentinel lymph node biopsy in
multicentric breast cancer. The experience of the European Institute of
Oncology. Eur J Surg Oncol 2006;32:50710.
9. Coombs N, Boyages J. Multifocal and multicentric breast cancer: does
each focus matter? J Clin Oncol 2005;23:7497502.
10. Tuttle TM, Colbert M. Subareolar injection of 99mTc facilitates sentinel lymph node identification. Ann Surg Oncol 2002;9:77 81.
11. Krag DN, Anderson SJ, Julian TB, et al. Technical outcomes of
sentinel lymph node resection and conventional axillary lymph node
dissection in patients with clinically node negative breast cancer:
results from the NSABP B-32 randomized phase III trial. Lancet
2007;8:881 8.